Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in children. In the absence of newborn screening, DMD is usually diagnosed when a child is 3 to 6 years of age. Early signs include delay in walking, frequent falling, and difficulty getting up from a sitting or lying position. Muscle deterioration continues to progress and, around the time they are 12 years of age, children with DMD become unable to walk. The disease is usually fatal in the teens or early 20s, most commonly due to severe respiratory or heart problems, or both. A milder form of the disease is known as Becker muscular dystrophy (BMD). The combined spectrum of these diseases is referred to as Duchenne/Becker muscular dystrophy (DBMD). The gene for DBMD is on the X chromosome, so DBMD affects males almost exclusively. For more information about DBMD,

Causes

In 1986, MDA-supported researchers identified the gene that, when flawed (a problem known as a mutation), causes DMD. They found that the gene’s failure to make a working version of the muscle protein dystrophin is the cause of the disease. Flawed dystrophin was also found in Becker muscular dystrophy (BMD), so that we now view DMD and BMD as variants of the same disease (DBMD). Patients with DBMD have decreased or abnormal dystrophin in their muscles. Further research has shown that dystrophin is found inside the muscle cell, where it helps support the cell membrane and minimizes injury related to the stress of muscle movement. Dystrophin could have other functions that have not yet been defined.

The particular gene that causes DBMD is found on the X chromosome. A functional copy of the gene is needed for normal muscle function. Males carry one X chromosome and one Y chromosome. Females carry two X chromosomes. Because the gene involved in DMD is on the X chromosome, it is called X-linked. Because males have only one X chromosome, a male carrying a copy with a DBMD mutation will have the condition. Because females have two copies of the X chromosome, a female can have one copy with a DBMD mutation and one functional copy. The functional copy is usually enough to compensate, and a female with a DBMD mutation usually has few or no symptoms. However, because she can pass the mutation on to her children, she is called a “carrier”. Each son born to a woman with a dystrophin mutation on one of her two X chromosomes has a 50% chance of inheriting the flawed gene and having DBMD. Each of her daughters has a 50% chance of inheriting the mutation and being a carrier.

Most boys with DBMD inherited the mutation from their mother. However, in about one-third of the patients with DBMD, the mother is not a carrier. Rather, there was a new mutation that formed in the egg that produced that child. In these cases, it is unlikely that future children will also have DBMD. However, in some cases, more than one egg was affected, in which case the chance of having another child with DBMD is increased.

Risk Factors

Family History

Diagnosis

Boys with DMD are usually diagnosed when they are around 3 to 6 years of age. In diagnosing DBMD (or any form of muscular dystrophy), a doctor begins by taking a patient and family history and performing a physical examination. Much can be learned from these, including the pattern of muscle weakness. The history and physical can suggest the diagnosis, even before any diagnostic tests are done. It is, however, important to do the diagnostic tests because other diseases have some of the same symptoms as DBMD. Following are brief descriptions of some of the more commonly performed tests or procedures recommended when DMD is suspected.

Creatine Kinase (CK) Test
Creatine kinase (CK) is a blood test. CK is normally found at high levels in the muscle and low levels in the blood. When there is injury to muscle or when there is a breakdown of the muscle membrane as in DBMD, the CK leaks out of the muscle and into the blood. In DBMD, the CK level is usually 20 to 200 times higher than normal. Very few other diseases cause such a high level of CK in the blood. The blood level of CK is increased from the time of birth in people with DBMD.

Many of the signs and symptoms of DMD are exceedingly difficult to detect in the early stages because many other conditions can produce similar signs and symptoms. Moreover, parents often are told by their doctor (or even several doctors) that their child will outgrow the clumsiness or other performance problems. Because of this difficulty in diagnosing, doctors are now being taught to do a CK test on young boys with these signs and symptoms, even if they do not find anything when they examine the child.

Genetic Testing
When a child is found to have an extremely high CK level, the next step usually is genetic testing on the blood to look for a mutation in the dystrophin gene. There are two types of genetic testing for DBMD. The first looks for large pieces of the dystrophin gene that are either missing (deleted) or duplicated. If a deletion or duplication is found in the dystrophin gene, then the diagnosis is confirmed and additional testing is generally not needed. Approximately 65% to 70% of patients with DBMD have a deletion or duplication that can be identified with this type of test.

The remaining 30% to 35% of DBMD patients have a tiny mutation that is much more difficult to find. In recent years, several approaches have been developed to identify these very small changes (point mutations). Currently, this type of testing is not routinely used to make a diagnosis, but is useful for genetic counseling.

The gene that carries the mutation for DBMD is the largest human gene that has been identified, which can make the task of identifying the flaw in the gene difficult. Hundreds of different mutations in the dystrophin gene have been found to result in DBMD.

Muscle Biopsy
Not all mutations in DBMD patients can be identified, so a negative genetic test does not necessarily mean that the patient does not have DBMD. Therefore, if the genetic testing is negative, then a muscle biopsy is usually recommended to make a diagnosis.

When seen under a microscope, muscle from patients with DBMD looks different from muscle of individuals who do not have DBMD. By examining a small sample of the patient’s muscle, doctors can tell a great deal about what is actually happening inside the muscle. Modern techniques can use the biopsy to distinguish MD from inflammation and other disorders. Other tests on the biopsy sample can provide information about which muscle proteins are present in the muscle cells, and whether they are present in the expected amounts and in the right places. During a muscle biopsy, a small piece of muscle (about the size of a pencil eraser) is removed and cut into very thin slices. These slices are stained with a series of special dyes to show the different types of muscle and are studied by a pathologist (a doctor who evaluates diagnostic tests). The slices can also be stained to see whether or not functional dystrophin is present in sufficient levels for normal muscle function.

Treatment

None

Prevention

Genetic testing before child is conceived and born.

Resources

Parent Project Muscular Dystrophy http://www.parentprojectmd.org 

Muscular Dystrophy Family Foundation http://www.mdff.org 

Muscular Dystrophy Association http://www.mdausa.org 

National Initiative for Families with Duchenne http://www.cnmcresearch.org/NIFD.asp 

National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/disorders/md.htm 

World Forum Neuromuscular Disease http://www.worldmuscleforum.org

References

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Mendell JR, Buzin CH, Feng J, Yan J, Serrano C, Sangani DS, et al. Diagnosis of Duchenne dystrophy by enhanced detection of small mutations. Neurol 2001;57:645–50.

Miller RG, Hoffman EP. Molecular diagnosis and modern management of Duchenne muscular dystrophy. Neurol Clin 1994;12:699–725.

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Grain L, Cortina-Borja M, Forfar C, Hilton-Jones D, Hopkin J, Burch M. Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls. Neuromuscul Disord 2001;11(2):186–91.

Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, Leschot NJ, et al. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study. Lancet 1999;353(9170):2116-9.

Politano L, Nigro V, Nigro G, Petretta VR, Passamano L, Papparella S, et al. Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA 1996;275(17):1335–8.